Non-Hodgkin Lymphoma
Philip J. Bierman
James O. Armitage
Non-Hodgkin lymphomas are a group of related malignancies of lymphocytes. Some lymphomas are among the most rapid growing and aggressive of all cancers, whereas others may be indolent and best managed with an initial period of observation. In the 1970s, it was recognized that aggressive non-Hodgkin lymphomas could sometimes be cured with combination chemotherapy. Since then, there have been significant increases in knowledge of the biology, immunology, and genetics of these disorders that have led to improvements in diagnosis, classification, and treatment. In many cases, non-Hodgkin lymphoma has served as a prototype for treatment of other forms of cancer.
Non-Hodgkin lymphomas are common malignancies and are often seen by primary care physicians as well as oncologists. Because lymphomas are frequently curable and often affect young individuals, a meticulous approach to diagnosis and staging is warranted. Any uncertainty regarding diagnosis should lead to review of biopsy material by an expert hematopathologist or to consideration of a repeat biopsy if the diagnosis is unclear.
EPIDEMIOLOGY
It is estimated that there will be 65,540 non-Hodgkin lymphomas diagnosed in the United States in 2010, and this diagnosis will account for 20,210 deaths.1 Approximately 4% of new cancers in men and women in the United States each year are non-Hodgkin lymphomas, and this diagnosis is responsible for approximately 4% of cancer deaths.
In 2007, the age-adjusted incidence rate2 for non-Hodgkin lymphoma in the United States was 20.22 per 100,000. Incidence rates are higher in males and higher in whites as compared with blacks and other ethnic groups. The lifetime risk of being diagnosed with lymphoma is 2.28% (1 in 44) for men and 1.92% (1 in 52) for females.1 The incidence of non-Hodgkin lymphoma increases with age and peaks in patients >80 years of age.2 There are significant geographic differences in lymphoma incidence and in the distribution of various histologic subtypes.3,4 The incidence rates are higher in western countries, whereas the incidence of peripheral T-cell lymphomas is higher in Asia.
Between 1975 and the mid-1990s, the incidence rate for non-Hodgkin lymphoma increased approximately 3% to 4% each year, although this rapid increase has slowed somewhat.2 This increase in lymphoma incidence before the mid-1990s has been called a lymphoma epidemic, and it has been observed in all parts of the world.3 Several hypotheses have been proposed to explain the increase in lymphoma incidence, although none are entirely satisfactory.5,6
ETIOLOGY
The cause of most cases of non-Hodgkin lymphoma is unknown, although most are associated with cytogenetic abnormalities that are characteristics of specific lymphoma subtypes (Table 42-1). These chromosomal translocations lead to overexpression of oncogenes that are involved in cell cycle regulation. An increased risk of lymphoma has been identified in first-degree relatives of patients with hematopoietic malignancies, and familial clusters of non-Hodgkin lymphoma have been described.7 It is unknown whether these clusters reflect a chance occurrence, a true genetic susceptibility, or a shared environmental exposure.
Immune Deficiency
Several inherited disorders are associated with an increased risk of developing lymphoma.8 These lymphomas are often associated with the Epstein-Barr virus (EBV). Ataxia telangiectasia is associated with a risk of lymphoma that may be more than 250-fold greater than normal individuals.9 A mutated ataxia-telangiectasia gene (ATM) has been cloned.10 The Wiskott-Aldrich syndrome is an X-linked recessive disorder associated with a risk of malignancy that is increased >100-fold.11 Similar increases in the risk of developing lymphoma are seen in patients with common variable immunodeficiency and severe combined immunodeficiency syndrome.12 The X-linked lymphoproliferative syndrome is characterized by a defective immune response to EBV. These patients have an increased risk of developing non-Hodgkin lymphoma as well as fatal infectious mononucleosis, aplastic anemia, and dysgammaglobulinemia. Patients with this disorder have mutations in the SH2D1A gene.13
Acquired immunodeficiency states are also associated with an increased risk of lymphoma. Patients with AIDS have a markedly increased risk of developing lymphoma, although this risk has diminished with the use of effective antiretroviral therapy.14 Patients also have a markedly increased risk of lymphoma following solid organ transplantation. These posttransplant lymphoproliferative disorders often result from EBV-transformed B-cell clones that proliferate because of medications used to suppress T-cell immunity and prevent organ rejection.15 Registry-based studies and case-control studies show that the risk of developing non-Hodgkin lymphoma is increased as much as 2.5-fold in patients with rheumatoid arthritis.16 Patients with
Sjögren syndrome have a 30- to 40-fold increased risk of developing lymphoma.17 These lymphomas are frequently marginal zone lymphomas that occur in the salivary glands and other extranodal sites. The risk of lymphoma is also increased in patients with systemic lupus erythematosus, and the incidence of thyroid lymphoma is increased in patients with Hashimoto thyroiditis. Patients with celiac disease have an increased incidence of enteropathy-associated T-cell lymphoma.
Sjögren syndrome have a 30- to 40-fold increased risk of developing lymphoma.17 These lymphomas are frequently marginal zone lymphomas that occur in the salivary glands and other extranodal sites. The risk of lymphoma is also increased in patients with systemic lupus erythematosus, and the incidence of thyroid lymphoma is increased in patients with Hashimoto thyroiditis. Patients with celiac disease have an increased incidence of enteropathy-associated T-cell lymphoma.
Table 42-1 Common Cytogenetic Abnormalities Seen in Non-Hodgkin Lymphoma | |||||||||||||||||||||
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There is now increasing recognition that genetic differences manifest by polymorphisms in genes associated with immune function are associated with an increased risk of lymphoma.18
Infectious Agents
Approximately 95% of endemic Burkitt lymphomas and some cases of sporadic Burkitt lymphoma are associated with EBV.19 This virus is also associated with most posttransplant lymphoproliferative disorders, lymphomas associated with congenital immunodeficiency, and AIDS-associated lymphomas. The human T-cell lymphotropic virus type I (HTLV-I) was the first human retrovirus associated with malignancy. The HTLV-I virus is associated with adult T-cell leukemia/lymphoma (ATL), which is most common in southern Japan, South America, Africa, and the Caribbean. The virus is transmitted by means of sexual contact, breast-feeding, and transfusions. Human herpesvirus 8 (HHV-8) was originally discovered in Kaposi sarcoma lesions and is seen in primary effusion lymphomas.20 This virus is also associated with multicentric Castleman disease. There is evidence linking the hepatitis C virus with lymphoplasmacytic lymphomas and other types of non-Hodgkin lymphoma.21 These lymphomas may regress with antiviral therapy.
Several lines of evidence link the bacteria Helicobacter pylori to gastric lymphomas of mucosa-associated lymphoid tissue (MALT).22 Colonization with H. pylori leads to chronic antigenic stimulation, which results in gastritis and the emergence of malignant B-cell clones. Other bacteria associated with MALT lymphomas in other locations include Campylobacter jejuni, Borrelia burgdorferi, and Chlamydia psittaci.22
Occupational and Environmental Risks
Occupational exposure may be a risk factor for developing lymphoma. Several analyses have demonstrated an increased risk of developing non-Hodgkin lymphoma in agricultural workers.23 This risk is felt to be related to phenoxy acid herbicide exposure, although conflicting data have been published. The risk of non-Hodgkin lymphoma may also be related to high-fat diets.24 Patients treated for Hodgkin lymphoma have a risk of developing non-Hodgkin lymphoma that is increased as much as 20-fold.25
CLASSIFICATION
Accurate and reproducible classification is necessary to compare patients, predict outcome, guide treatment, and study the biology of non-Hodgkin lymphomas. In the 1960s and 1970s, six major classification systems for non-Hodgkin lymphoma were used. The Rappaport classification system classified lymphomas according to growth pattern as well as size and shape of cells.26 Later, Lukes and Collins27 recognized that lymphomas were solid tumors of the immune system and developed a classification system based on immunologic characteristics as well as size and shape. In Europe, the Kiel classification was most commonly used. This system classified lymphomas according to a combination of immunologic and morphologic characteristics.28
The large number of classification systems led the National Cancer Institute to sponsor a study that gathered expert pathologists to classify 1,175 cases of non-Hodgkin lymphoma according to each of the six classification systems that were most widely used.29 They developed a Working Formulation that separated lymphomas into 10 major categories that allowed translation among the six classification systems that were in common use. The Working Formulation had several important deficiencies, and the International Lymphoma Study Group (ILSG) proposed a Revised European-American Classification of Lymphoid Neoplasms.30 This classification system incorporated morphology, immunophenotype, genetic
features, and clinical features to separate lymphomas into categories that represented distinct clinical entities. This attempt to define true disease entities without focusing on morphologic subtleties represented a departure from previous classification systems.
features, and clinical features to separate lymphomas into categories that represented distinct clinical entities. This attempt to define true disease entities without focusing on morphologic subtleties represented a departure from previous classification systems.
The ILSG classification of non-Hodgkin lymphomas has been modified and incorporated into the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, which was modified in 2008 to include new entities defined by clinical criteria, genetic criteria, morphology, and immunophenotype (Table 42-2).31 This classification also uses new technology such as gene expression profiles to classify tumors.32,33,34 The WHO classification system has been accepted by proponents of other classification systems and represents true international consensus on lymphoma classification.
Table 42-2 WHO Classification of Non-Hodgkin Lymphoma | ||||||||
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STAGING
Lymphoma patients require a meticulous staging evaluation. Accurate staging gives important prognostic information and is used to select appropriate treatment. In addition, staging allows patients to be reevaluated after treatment to determine response to therapy. Stage is also an important prognostic factor that helps us to compare clinical characteristics of patients in different studies.
Useful staging studies include a careful physical examination, hemogram, chemistry profile that includes lactate dehydrogenase (LDH) level, serum β2-microglobulin, chest radiograph, bone marrow biopsy, and CT scans. Positron emission tomography (PET) scans are being used with increasing frequency to identify occult areas of lymphoma and to distinguish residual disease from fibrosis following treatment.
The most common staging system is the Ann Arbor classification that was developed for patients with Hodgkin lymphoma (Table 42-3).35 This system separates patients into four stages on the basis of anatomic sites of disease. Imperfections of the Ann Arbor classification have led to other systems that use additional variables to divide non-Hodgkin lymphoma patients into clinically important prognostic groups.
PROGNOSTIC FACTORS
Various clinical and biologic factors yield valuable information regarding the prognosis of patients with non-Hodgkin lymphoma. These factors can be divided into those related to the host or tumor itself, those related to response to tumor, and those related to a patient’s ability to tolerate therapy.36 The most widely used prognostic index for non-Hodgkin lymphoma is the International Prognostic Index (IPI) (Table 42-4).37 Five features (age, serum LDH, performance status, anatomic stage, and several extranodal sites) are used, and patients can be separated into four risk groups based on the number of these adverse prognostic factors that are present at diagnosis. An age-adjusted index using LDH, performance status, and stage was also developed for patients ≤60 years of age (Table 42-4). The IPI is able to predict complete remission rate, relapse-free survival, and overall survival, and it was shown to be more accurate than Ann Arbor stage alone. A revised IPI has been developed because of the improved survival of diffuse large B-cell lymphoma patients with rituximab-based therapy.38 A Follicular Lymphoma International Prognostic Index (FLIPI) is also widely used.39 This index incorporates five features (age, anatomic stage, hemoglobin level, serum LDH, and several extranodal sites) to separate patients into three prognostic
groups (Table 42-5). A FLIPI-2 incorporating β2-microglobulin level, size of involved nodes, bone marrow involvement, hemoglobin level, and age has also been developed.40 Indices for mantle cell lymphoma and peripheral T-cell lymphomas have been devised.41,42
groups (Table 42-5). A FLIPI-2 incorporating β2-microglobulin level, size of involved nodes, bone marrow involvement, hemoglobin level, and age has also been developed.40 Indices for mantle cell lymphoma and peripheral T-cell lymphomas have been devised.41,42
Table 42-3 Ann Arbor Staging Classification | |||||||||
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Table 42-4 Outcome According to Risk Group Defined by the IPI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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An increasing number of additional clinical, molecular, and genetic prognostic factors have been reported for follicular lymphomas and diffuse large B-cell lymphomas.43,44 The rapidity of response to therapy is also an important prognostic factor. Patients who respond slowly to initial therapy have inferior outcomes and may be candidates for more aggressive treatment.45 The use of interim PET scanning is an important tool to identify slow responders who may have an inferior prognosis. Several ongoing trials are investigating the use of response-adapted therapy to alter lymphoma treatment based upon mid-cycle interim PET scan results.46
PRINCIPLES OF THERAPY
Surgery is rarely used for lymphoma treatment, although lymphomas involving extranodal sites can sometimes be cured with resection. Non-Hodgkin lymphomas are highly radiosensitive, and
radiation can be used as primary therapy or combined with chemotherapy. Radiation therapy is often used palliatively to control localized sites of relapse. Lymphomas were among the first malignancies shown to be curable with combination chemotherapy.
radiation can be used as primary therapy or combined with chemotherapy. Radiation therapy is often used palliatively to control localized sites of relapse. Lymphomas were among the first malignancies shown to be curable with combination chemotherapy.
Table 42-5 Outcome According to Risk Group Defined by the FLIPI | ||||||||||||||||||
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Non-Hodgkin lymphomas may behave in an indolent manner or aggressively. This behavior may be independent of the histology and often depends on the site of disease, patient age, and comorbidity. Sometimes the best management option is an observation period to determine the tempo of disease progression, while other patients, such as those with spinal cord compression or CNS involvement, require aggressive therapy on an emergent basis. Three fundamental questions should be asked before beginning therapy for any patient:
Will this treatment improve symptoms?
Does this treatment have curative potential?
Can this treatment prolong survival?
FOLLICULAR LYMPHOMA
This section deals with patients having follicular lymphoma grades 1 and 2. It is generally agreed that these patients can be considered as a single category. Many physicians feel that follicular lymphoma grade 3 has a different natural history and should be treated in the same way as diffuse large B-cell lymphoma.47,48
Localized Disease
Approximately 5% to 15% of patients with follicular lymphoma will have localized disease at diagnosis. These patients may experience prolonged disease-free survival with a watchand-wait approach, especially if they are free of disease after diagnostic biopsy.49,50,51 The 10-year survival in a selected group of patients with stage I to II follicular lymphoma managed with a watch-and-wait approach at Stanford was estimated at 85%.51 The median survival was 19 years, and 56% were still untreated after 10 years. This approach may be reasonable for some asymptomatic patients who do not desire therapy, are elderly, or have other medical conditions.
Involved-field radiation therapy for localized low-grade lymphoma is associated with 10-year relapse-free survival rates of approximately 50%.52,53,54 It is unclear whether survival is improved with the addition of chemotherapy. Investigators from M.D. Anderson Cancer Center performed a prospective trial of combined-modality treatment for patients with stage I to II low-grade follicular lymphoma.55 Patients received cyclophosphamide, vincristine, prednisone, and bleomycin (COP-bleo) or CHOP-bleo (COP-bleo and doxorubicin) combined with involved-field radiation. At 10 years, the time to treatment failure was estimated to be 72%, and overall survival was estimated at 80%. A prospective randomized British National Lymphoma Investigation (BNLI) trial found no improvement in disease-free survival or overall survival when chlorambucil was added to involved-field radiation therapy in patients with localized low-grade lymphoma.56
Advanced Stage
Various treatment options are available for patients with follicular lymphoma who have advanced-stage disease at diagnosis. The National LymphoCare Study documented wide variation in management of US patients with newly diagnosed follicular lymphoma.57 Nevertheless, the overall survival of patients with follicular lymphoma has improved and more than 70% of patients survive 10 years in the United States.58,59
Definite indications for therapy in patients with follicular lymphoma include rapidly progressing or symptomatic adenopathy or splenomegaly, symptomatic effusions, and cytopenias. In addition, patients frequently request therapy. A watch-and-wait approach is appropriate for asymptomatic patients, especially if they are elderly or have comorbid conditions.60,61 There is little evidence that survival is shortened by deferral of treatment until patients are symptomatic. A trial from the National Cancer Institute randomized patients with advanced low-grade lymphoma to observation or to treatment with ProMACE-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, prednisone) combined with total nodal irradiation.62 The 4-year disease-free survival was estimated at 51% following aggressive therapy as compared with 12% after observation (P < .001), although overall survival advantages were not seen. A three-armed trial conducted by the French Groupe d’Etude des lymphomes de l’Adulte (GELA) cooperative group randomized follicular lymphoma patients with low tumor burden to treatment with observation, prednimustine, or interferon-α.63 Significant differences in overall survival were not observed. Patients in another BNLI trial were randomized between oral chlorambucil and a watch-and-wait approach.64 The median survival rates in the two groups were 6.7 and 5.9 years, respectively (P = .44).
Single-agent cyclophosphamide or chlorambucil, or combination therapy with cyclophosphamide, vincristine, and prednisone (CVP), may be appropriate for some patients.65 Numerous prospective-randomized trials have compared treatment with different chemotherapeutic regimens for patients with lowgrade lymphomas.66,67,68,69,70,71 Although progression-free survival is
often increased with more aggressive therapies, significant overall survival advantages have not been demonstrated.
often increased with more aggressive therapies, significant overall survival advantages have not been demonstrated.
The purine analogs, fludarabine, 2-deoxycoformycin, and 2-chlorodeoxyadenosine, have single-agent response rates of 25% to 50% in previously treated patients with low-grade lymphomas.72 The overall response rate was 65% when single-agent fludarabine was used for untreated follicular lymphoma.73 The combination of fludarabine, mitoxantrone, and dexamethasone has an overall response rate of 70% to 90% for newly diagnosed follicular lymphoma patients.74,75 Similar results have been seen with the combination of fludarabine and cyclophosphamide.76,77
A GELA trial randomized elderly patients between fludarabine, or to treatment with cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP) combined with interferon.78 The 2-year actuarial survival was 62% in the fludarabine arm, as compared with 77% in the other arm (P < .05). A phase III trial conducted by the European Organization for Research and Treatment of Cancer compared single-agent fludarabine with CVP for patients with stage III and IV low-grade non-Hodgkin lymphoma.79 The response rate was higher in the fludarabine arm (70% vs. 52%; P < .001), although there were no significant differences in failure-free survival or overall survival.
A prospective trial from M.D. Anderson Cancer Center compared the combination fludarabine, mitoxantrone, and dexamethasone with a 13-drug alternating triple therapy (ATT) regimen.80 The 5-year failure-free survival was estimated at 41% with the fludarabine-based regimen, as compared with 50% for the ATT regimen (P = .02). No significant difference in 5-year survival was noted, however. In another trial, the combination of fludarabine and mitoxantrone was compared with cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP).81 The complete response rates were 68% and 42%, respectively (P = .003), although overall survival was not significantly different. Another phase III trial compared fludarabine and mitoxantrone with CHVP in elderly patients with indolent non-Hodgkin lymphoma.82 The 4-year failure-free survival was 42% in the fludarabine-treatment arm, as compared with 10% for patients treated with CHVP (P = .0001). No significant differences in overall survival were noted.
Interferon
Interferon has significant single-agent activity in patients with relapsed and refractory follicular lymphoma.83 Although rarely used, randomized trials have demonstrated improvements in progression-free survival84,85,86 and overall survival84 when combined with chemotherapy. Benefits from interferon have not been seen in all studies.87 A meta-analysis suggested that interferon-α2 administration is associated with improved survival for follicular lymphoma when used in combination with relatively intensive initial chemotherapy and when patients receive doses of at least 36 × 106 units per month.88
Monoclonal Antibodies
Rituximab is a chimeric human-mouse anti-CD20 antibody that has revolutionized the treatment of follicular lymphoma. Phase II trials demonstrated response rates of approximately 50% in previously treated patients with follicular lymphoma.89 Median response duration is approximately 12 months and prolonged remissions are seen, although no plateau in diseasefree survival is evident. Rituximab responses can be seen in chemotherapy-resistant patients and in patients who have relapsed after autologous hematopoietic stem cell transplantation (AHSCT). Patients who relapse after rituximab treatment will often respond to a second course of treatment.90 Prolonged event-free survival has been observed when singleagent rituximab has been used as initial therapy for untreated patients.91,92,93
Randomized trials have demonstrated significant increases in response rate, progression-free survival, and overall survival when rituximab is combined with conventional chemotherapy regimens.94,95,96,97 A German trial randomized patients with follicular lymphoma between treatment with CHOP and R (rituximab)-CHOP.94 The estimated 2-year survival was 90% and 95%, respectively (P = .016). Follicular lymphoma patients in an East German trial were randomized to treatment with mitoxantrone, chlorambucil, and prednisolone (MCP) or R-MCP.95 The actuarial 4-year survival rates were 74% and 87%, respectively (P = .0096). A third prospective trial for follicular lymphoma patients compared CVP with R-CVP.96 The estimated 4-year survival rates were 77% and 83%, respectively (P = .029). Although there is disagreement about the optimal upfront chemotherapy regimen for follicular lymphoma,57 there is consensus that rituximab should be added to chemotherapy.
Additional rituximab following CHOP or fludarabine-based therapy can increase the complete response rate.81 The use of maintenance rituximab for patients with follicular lymphoma improves outcomes with various regimens. A randomized Swiss trial with single-agent rituximab used in the upfront and relapse settings for patients with follicular lymphoma investigated the value of rituximab maintenance93 administered at months 3, 5, 7, and 9. The median event-free survival was prolonged from 13 to 24 months with maintenance therapy (P < .001). An intergroup trial randomized patients with follicular lymphoma to observation or maintenance rituximab following treatment with CVP.98 Maintenance rituximab was administered weekly for 4 weeks, every 6 months (four courses). The estimated 3-year progression-free survival was 33% following CVP and 64% following CVP with maintenance rituximab (P = 9.2 × 10-8). Overall survival rates were estimated at 86% and 91%, respectively (P = .08).
The question of whether maintenance rituximab is beneficial for patients with follicular lymphoma who receive rituximab with upfront chemotherapy was addressed in the PRIMA study.99 Patients in this trial received R-CVP, R-CHOP, or fludarabine, cyclophosphamide, and mitoxantrone (R-FCM). Responders were then randomized between observation and maintenance rituximab administered every 8 weeks for 2 years. The estimated 2-year progression-free survival was 66% for the observation arm and 82% with maintenance rituximab (P < .0001). Differences in overall survival were not observed. Rituximab has been approved for maintenance
therapy following upfront chemoimmunotherapy for follicular lymphoma. Rituximab increases the response rate with salvage chemotherapy for follicular lymphoma and prolongs progression-free survival.100,101 Rituximab maintenance prolongs progression-free survival following salvage chemotherapy for follicular lymphoma.101 A meta-analysis showed a significant improvement in overall survival when maintenance rituximab was used for patients with relapsed follicular lymphoma (hazard ratio 0.68).102
therapy following upfront chemoimmunotherapy for follicular lymphoma. Rituximab increases the response rate with salvage chemotherapy for follicular lymphoma and prolongs progression-free survival.100,101 Rituximab maintenance prolongs progression-free survival following salvage chemotherapy for follicular lymphoma.101 A meta-analysis showed a significant improvement in overall survival when maintenance rituximab was used for patients with relapsed follicular lymphoma (hazard ratio 0.68).102
Additional anti-CD20 antibodies as well as antibodies directed at other antigenic targets are under development.103 Ofatumumab is a monoclonal antibody that targets a novel CD20 epitope.104 This agent is approved for the treatment of patients with refractory chronic lymphocytic leukemia. A phase I/II study demonstrated clinical activity with ofatumumab for patients with relapsed and refractory follicular lymphoma, even if they had previously received rituximab.105
The radiolabeled antibodies 90Y-ibritumomab tiuxetan and 131I-tositumomab are approved for patients with relapsed and refractory low-grade, follicular, or transformed B-cell lymphomas. Response rates of 50% to 80% have been observed for patients with follicular and other indolent lymphomas, including patients who were refractory to chemotherapy and rituximab.106,107,108 Response rates may be higher than those of rituximab alone.108 Radiolabeled antibodies have been used as initial therapy for follicular lymphoma.109 Radiolabeled antibodies have also been tested in phase II trials following primary chemotherapy with CVP and CHOP.110,111 In a phase III trial, follicular lymphoma patients who responded to primary chemotherapy were randomized between observation or to treatment with 90Y-ibritumomab tiuxetan consolidation.112 Additional therapy with the radiolabeled antibody prolonged the median progression-free survival from 13.3 to 36.5 months (P < .0001), although no overall survival differences were reported. This agent is now approved for use in untreated patients with follicular lymphoma who respond to upfront therapy.
New Drugs
Bendamustine administered as a single agent or in combination with rituximab yields response rates of 80% to 90% in patients with relapsed and refractory follicular lymphoma and other indolent subtypes.113,114,115 In a prospective trial patients with untreated follicular lymphoma and mantle cell lymphoma were randomized between treatment with R-CHOP and R-bendamustine.116 The median progression-free survival was 46.7 months following R-CHOP and was not yet reached for patients receiving bendamustine (P = .0002). Patients in the bendamustine arm also had significantly less toxicity. The proteasome inhibitor bortezomib, administered alone or in combination with rituximab, is also active for patients with relapsed and refractory indolent lymphomas.117,118 The immunomodulatory agent, lenalidomide, may also induce durable responses for patients with relapsed and refractory follicular lymphoma.119 Ongoing trials are testing combinations of these newer agents.
Hematopoietic Stem Cell Transplantation
Prospective randomized trials have investigated the role of AHSCT as part of initial therapy for patients with follicular lymphoma. 120,121,122,123 Although progression-free survival is prolonged, overall survival advantages have not been demonstrated. Only one of these trials utilized rituximab treatment,122 and this approach cannot be recommended outside of a clinical trial. A single randomized trial performed prior to the introduction of rituximab showed that AHSCT was superior to conventional salvage chemotherapy for patients with chemotherapysensitive relapsed follicular lymphoma.124 Additional reports have demonstrated that long-term progression-free survival can be observed in approximately 40% to 50% of patients with relapsed follicular lymphoma following AHSCT.125,126,127,128 Allogeneic hematopoietic stem cell transplantation has the potential to cure patients with follicular lymphoma, although the morbidity and mortality may be high.129
DIFFUSE LARGE B-CELL LYMPHOMA
Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. The WHO classification separates this histology into a large number of variants based upon morphology, molecular signature, immunohistochemistry, and clinical characteristics.31 In addition, borderline cases with characteristics of Burkitt lymphoma and Hodgkin lymphoma are described. In the future, it is unlikely that these different types of diffuse large B-cell lymphomas will all be treated in the same manner. We are entering an age of personalized or customized therapy where treatment decisions will be based upon these differences in the tumor as well as genetic differences in the host.
Localized Disease
As many as 30% of diffuse large B-cell lymphoma patients have stage I or II disease. These patients were historically treated with radiation therapy, but subsequent trials demonstrated that adjuvant chemotherapy could improve outcome.130 Prolonged disease-free survival was later reported with full courses of anthracycline-based therapy, and several trials demonstrated 5-year disease-free survival rates of 80% to 90% with a brief course of chemotherapy followed by involved-field radiotherapy.131,132,133
More recent trials have examined issues related to use of radiation, duration of chemotherapy administration, and improvements in chemotherapeutic regimens for these patients. A Southwest Oncology Group (SWOG) trial randomized patients with stage I or nonbulky stage II disease to receive eight cycles of CHOP or to receive three cycles of CHOP followed by involved-field radiotherapy.134 Overall survival rates were 82% and 72%, respectively (P = .02), although these survival differences disappeared with longer follow-up.135 A subsequent SWOG phase II trial examined the use of three cycles of R-CHOP and involved-field radiotherapy for patients with limited-stage aggressive lymphomas.136 The 4-year progression-free survival and overall survival were estimated to be 88% and 92%, respectively.
A retrospective analysis from the British Columbia Cancer Agency also examined the results of patients with limited-stage diffuse large B-cell lymphoma who were treated with an abbreviated course of anthracyline-based chemotherapy followed by involved-field irradiation.137 The 10-year progression-free survival was estimated at 74%. An Eastern Cooperative Oncology Group trial randomized patients with bulky or extranodal stage I and stage II aggressive non-Hodgkin lymphoma who responded to eight cycles of CHOP to observation or involvedfield radiation.138 The 6-year failure-free survival was estimated at 70% for patients who received irradiation, as compared with 53% for those followed with observation (P = .05). No significant differences in overall survival were observed. The GELA performed a prospective trial for patients with localized aggressive lymphoma that compared three cycles of CHOP followed by involved-field irradiation, with three cycles of ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone; Table 42-6) and sequential consolidation.139 The 5-year event-free survival was estimated at 74% following CHOP and irradiation and 82% following ACVBP (P < .001). Actuarial 5-year overall survival rates were 81% and 90%, respectively, (P = .001).
Table 42-6 Combination Chemotherapeutic Regimens for Newly Diagnosed Diffuse Large B-Cell Lymphoma | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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